In industrialized countries, characterized by a sedentary lifestyle and high-caloric diet, energy balance is often deregulated leading to the development of obesity, dyslipidemia, hyperglycemia, and insulin resistance (type 2 diabetes). Among other organs, adipose tissue is an important regulator of energy balance (Langin, 2010). There are two major types of adipose tissue in mammals, white adipose tissue (WAT) and brown adipose tissue (BAT), which are present in different compartments and show distinct metabolic characteristics. Unilocular WAT is highly adapted to store excess energy in the form of triglycerides and is mainly located in the abdominal and subcutaneous areas. Conversely, multilocular cells from BAT, which are mainly located in the interscapular area (iBAT), oxidize chemical energy to produce heat as a defense against hypothermia and obesity (Himms-Hagen, 1990; Langin, 2010). Fatty acid oxidation and heat production by brown adipocytes is due to the intense metabolic activity of mitochondria, which express uncoupling protein 1 (Ucp1) (Ricquier and Bouillaud, 2000). WAT and BAT have long been assumed to have the same embryonic origin. However, recent evidence suggests that brown and white adipocytes are derived from two different precursors (Seale et al., 2008). These precursors can be discriminated by the presence or absence of the transcription factor myogenic factor 5 (Myf5), with brown adipocytes being derived from Myf5-positive and white adipocytes derived from Myf5-negative cells, respectively (Seale et al., 2008). In response to environmental cues such as cold or treatment with β3-adrenergic agonists, appearance of brown fat-like cells has been observed in mouse WAT (Himms-Hagen et al., 1994; Himms-Hagen et al., 2000; Young et al., 1984). These brown fat-like cells are called beige or brite cells. Interestingly, these beige fat cells are not derived from Myf5-expressing precursors (Seale et al., 2008), raising questions about their origin. It has been speculated that beige cells might originate from differentiation of a specific pool of precursor cells already present in WAT (Seale et al., 2011; Wu et al., 2012). Alternatively, beige fat cells could arise from direct conversion of white adipocytes (Granneman et al., 2005; Himms-Hagen et al., 2000; Loncar, 1991). Recently, Wu and colleagues proposed that beige cells exhibit a gene expression pattern distinct from either white or brown fat and that previously identified brown fat deposits in adult humans are indeed composed of beige adipocytes (Wu et al., 2012). However, it is neither known whether beige adipocytes constitute metabolically active fat cell nor are the transcriptional cascades that control the transformation of white to beige adipose tissues have been determined so far.
Over the last decade, evidence accumulated that epigenetics contribute to regulation of adipogenesis. In particular, posttranslational modifications of histone H3 lysines have been linked to either transcriptional activation or repression, depending on the modified residue. Methylation of lysine 4 in histone H3 (H3K4) correlates with gene activation, whereas methylation of lysine 9 or 27 in histone H3 (H3K9 or H3K27, respectively) is associated with transcriptional repression. As an example illustrating the key role of lysine methylation in adipocyte differentiation, it was reported that H3K4 methylation was required for Pparg and C/ebpa expression and thus positively regulates adipogenesis (Cho et al., 2009). In contrast, methylation of H3K27 by the methytransferase Ezh2 promotes adipogenesis by repressing the Wnt signaling (Wang et al., 2010). Lysine-specific demethylase 1 (LSD1), the first histone lysine demethylase described, is an amine oxidase that mediates histone demethylation via a FAD-dependent oxidative reaction. It has been shown that LSD1 selectively removes mono- and dimethyl groups from H3K4 or H3K9, thereby causing either repression or activation of gene transcription (Garcia-Bassets et al., 2007; Lee et al., 2005; Metzger et al., 2010; Metzger et al., 2005; Shi et al., 2004; Wang et al., 2009a; Wang et al., 2009b) (Zhu Ms). Recent in vitro studies suggest that LSD1 might play a role during fat cells differentiation in vitro (Hino et al., 2012). Hino et al. observe upregulation of LSD1 protein levels in mice on a high fat diet. In addition, their ex vivo experiments with adipocytes from mice on a high fat diet suggest that energy expenditure genes are upregulated upon knockdown of LSD1. This teaches away from the present invention.